A clinically distinguishing feature of multiple myeloma (MM) is focal tumor growth detectable by MRI as focal lesions; this tumor growth is associated with increased resistance to chemotherapy and often osteolytic bone disease. Our preliminary work suggests that focal lesions, osteolytic bone disease, and dissemination to extramedullary disease are associated with molecular events resulting from suppression of Wnt/Beta-catenin signaling and from interactions between p-catenin and cadherin that mediate cell adhesion. Our long-term objective is to thoroughly understand the relationship between Wnt/Beta-catenin signaling and myeloma pathogenesis, with the ultimate goal of uncovering novel therapeutic approaches to control myeloma growth and improve survival and quality of life of patients with MM. We hypothesize that deregulation of Wnt/Beta-catenin signaling in both the microenvironment and the myeloma tumor cell is a fundamental and critical event in the natural history of MM. Therefore, control of this signaling axis may represent a paradigm shift in myeloma therapy. We will pursue this broad hypothesis through the following specific aims: (Aim 1) Verify that elevated transcription of DKKI in myeloma tumor cells is related to polymorphisms/mutations in the DKKI promoter; (Aim 2) Examine the roles of E- and N-cadherin and their interactions with Beta-catenin in MM pathogenesis and determine if they represent viable therapeutic targets; (Aim 3) Determine whether bone-anabolic effects of bortezomib treatment result from induction of Beta-catenin signaling in mesenchymal stem cells and osteoblasts; (Aim 4) Establish the derivation of a novel CYR61 isoform in MM and determine the in vitro and In vivo effects of this and native CYR61 on myeloma growth and bone disease. Comprehensive understanding of the molecular events surrounding dysregulation of Wnt/Beta-catenin signaling in MM will potentially provide the foundation for innovative therapeutic strategies to control growth of myeloma.